Reduced levels of neurotransmitters including acetylcholine occur in dementias of the Alzheimer type. In particular, a deficit in acetylcholine-mediated transmission is thought to contribute to the cognitive and neurobehavioral abnormalities associated with these disorders. Accordingly, drugs known to augment cholinergic transmission in the CNS are the mainstay of current therapy. In addition, other diseases of the nervous system also involve decreased cholinergic transmission and are referred to as “hypocholinergic syndromes of the nervous system.” Such diseases include, but are not limited to, Mild Cognitive Impairment (MCI), Lewy Body Disease dementia (LBD), Parkinson disease dementia (PDD), post-stroke dementia, vascular dementia, Traumatic Brain Injury, Down's syndrome, Anorexia Nervosa, and schizophrenia. It is well documented that schizophrenic patients experience cognitive disturbances that are not well addressed by current medications (reviewed in Foster et al, 2014). CRAs have been reported to dose-dependently improve the cognitive disturbances associated with schizophrenia, but the effect of CRAs is of limited extent and dose-dependent side effects prevent further increases in the CRA doses.
Acetylcholinesterase inhibitors (AChEIs) are now not only part of the standard of care for patients suffering from a dementia of the Alzheimer type, but are also widely used off-label for various other chronic progressive hypocholinergic disorders of the nervous system. AChEIs have the enhancement of acetylcholine-mediated neurotransmission as a general mechanism of action. All act in the human CNS to increase and prolong the availability of acetylcholine by inhibiting its degrading enzyme, acetylcholinesterase (AChE). Four AChEIs have been approved by the U.S. FDA for the treatment of dementias of the Alzheimer type: tacrine, donepezil [Aricept®], rivastigmine [Exelon®] and galantamine [Razadyne®]. Rivastigmine has also been approved for the treatment of Parkinson's disease dementia. AChEIs are available in various formulations including immediate release forms such as tablets, capsules and solutions as well as rapid dissolving and extended release forms for oral administration as well as those for parenteral (e.g. transdermal) administration.
Unfortunately, however, none of the currently available AChEIs offers more than modest clinical benefit for patients suffering from any of the aforementioned dementing disorders, even when these medications are administered at their maximum safe and tolerated doses. This is the first problem limiting the success of current AChEI therapy of Alzheimer type dementias.
A second problem limiting the success of current AChEI therapy of Alzheimer type dementias is that, even at recommended amounts, all these drugs produce dose limiting adverse reactions, mainly if not exclusively, by over-stimulating peripheral cholinergic receptors of the muscarinic type. As a result, signs and symptoms of untoward gastrointestinal, pulmonary, cardiovascular, urinary, and other systems dysfunction occur. These side effects commonly include, anorexia, nausea, vomiting, diarrhea, abdominal pain, weight loss; increased bronchial secretions, dyspnea, bronchoconstriction and bronchospasm; bradycardia, supraventricular cardiac conduction abnormalities, vasodilation, hypotension, dizziness and syncope; urinary bladder spasm, increased urinary frequency, and incontinence; flushing and diaphoresis; fatigue, headache, lachrymation, miosis, and loss of binocular vision (Physicians' Desk Reference 2008, Thomson PDR, Montvale, N.J.).
These problems linked to the use of the AChEIs have been solved by combining said AChEI with a nsPAChA (U.S. Pat. No. 8,404,701, the disclosure of which is incorporated herein in its entirety) or with a non-anticholinergic antiemetic agent (U.S. Pat. No. 8,877,768, the disclosure of which is incorporated herein in its entirety), these combinations allowing a great increase of the administered AChEI doses with attending increase in plasma and brain concentrations of the AChEI, and consequent possibility of increasing anti-dementia efficacy.
Another way to increase the cholinergic transmission in the brain is to stimulate post-synaptic cholinergic receptors by administering an agonist of the muscarinic receptors, but the results were generally disappointing. However, the efficacy of one such product, xanomeline, that stimulates muscarinic receptors in the brain and in the periphery was studied in patients with Alzheimer disease in a 6-month double-blind, placebo-controlled, parallel group trial. Compared to placebo, xanomeline was shown to significantly improve cognitive and behavioral symptoms of Alzheimer disease (Bodick et al., Arch. Neurol., 54: 465-473, (1997), which is incorporated herein in its entirety), but also caused dose-dependent unacceptable side effects, including bradycardia, gastro-intestinal distress, excessive salivation, and sweating. Such side effects prevented the use of doses of xanomeline that could achieve maximum anti-dementia efficacy and reflect stimulation of cholinergic receptors outside the brain. As described in the present invention, utilizing a drug that can antagonize the dose-limiting adverse events of a CRA without preventing anti-dementia efficacy enables the full antidementia efficacy of the CRA.
Dose-limiting adverse events attending the use of drugs that stimulate cholinergic transmission, such as xanomeline and other CRAs, appear to primarily reflect the excessive stimulation of peripheral cholinergic receptors, especially those of the muscarinic type (mAChRs), such that in both healthy volunteers and Alzheimer's patients many of these side effects have been reported for xanomeline; in the patient population this led to a discontinuation rate higher than 50% while the effects on cognition were not as robust and mainly seen at the highest doses tested (Mirza et al. CNS Drug Reviews Vol. 9, No. 2, pp. 159-186, 2003). In this review, the authors report that the maximal tolerated dose of orally administered xanomeline is 75 mg three times/day, i.e. 225 mg/day, even though some individuals tolerated a dose of 110 mg three times/day, taken with food. These authors also suggest that xanomeline would be a good antipsychotic.
In conclusion, the development of all of the above CRAs was discontinued because the results of the studies were disappointing not for a basic muscarinic inactivity of the products but because said products were inefficacious in patients and, in addition, induced dose-limiting, irreducible adverse effects.
In a review published in NEUROLOGY, 49, July 1997, by H. Robert Brashear, MD, of the book “Muscarinic Agonists and the Treatment of Alzheimer Disease” (Edited by Abraham Fisher—R. G. Landes, 1996), the reviewer concluded his comment as follows: “It will be of interest to most clinicians who treat Alzheimer's disease and valuable to chemical researchers, basic neuroscientists, biochemists, and pharmacologists investigating cholinergic dysfunction and therapy”. Despite this clear interest and the extensive studies made on a series of compounds during the last two decades, none of the studied compounds became a drug for the treatment this disease for the reasons set forth above.
In addition, CRAs consisting of allosteric modulators of the M1-muscarinic acetylcholine receptor are extensively studied and are the object of copious patent and scientific literature.
A review by B. J. Melancon, J. C Tarr, J. D. Panarese, M. R. Wood and C. W. Lindsley published in Drug Discovery Today; Volume 18, Numbers 23/24, December 2013, “Allosteric modulation of the M1 muscarinic receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease” (Melancon et al.), the disclosure of which is incorporated herein by reference in its entirety, illustrates the role of the M1 receptor in Alzheimer's disease and in schizophrenia by referring to selected allosteric modulators of the M1 receptor.
This review also reports that the positive allosteric modulator MK-7622 entered Phase II clinical trials as an adjunct therapy to AChEIs in patients with AD. This positive allosteric modulator of the M1 receptor, 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one, is described in U.S. Pat. No. 8,883,810, the disclosure of which is incorporated herein by reference in its entirety.
Notwithstanding the previous aforementioned disappointing results and the recent progress of the scientific studies, the literature does not teach how to take advantage of the ubiquitous, potent activity of the muscarinic agonists safely. Thus, the problem of the effective and safe treatment of Alzheimer type dementia and in general of hypocholinergic disorders in the CNS such as schizophrenia, Down's syndrome, Tourette disease, tardive dyskinesia, Pick's disease, Huntington's chorea, and Friedrich's ataxia, with a muscarinic agonist, remains of primary importance.
An improvement in the treatment of Alzheimer type dementia is attained by a combined therapy associating a non-selective, peripheral anticholinergic agent, at a dose of from 20% to 200% the current daily doses, with an AChEI, at a dose up to about 6 times the maximal recommended dose of said AChEI. By such a treatment, a higher acetylcholinesterase inhibition in the CNS is achieved and greater relief of the symptoms of Alzheimer type dementia is enabled, by concomitantly decreasing concurrent adverse effects.
U.S. Pat. No. 8,877,768, discloses an improvement in the treatment of Alzheimer type dementia, which is attained by a combined therapy associating a non-anticholinergic-antiemetic agent, at a dose of from 50% to 300% the current IR daily doses, with an AChEI, at a dose up to 4 times the maximal recommended doses of said AChEI when administered alone.
Similarly, WO 2014/039637, the disclosure of which is herein incorporated by reference in its entirety, discloses increasing the blood levels of a concurrently administered AChEI with a non-selective peripheral anticholinergic agent, with the higher the dose of either the non-selective anticholinergic agent or the AChEI, the higher the increase of the AChEI blood levels. Thus, WO 2014/039637 uses high doses of both the non-selective, peripheral anticholinergic agent and of the AChEI in order to ameliorate the symptoms of Alzheimer's dementia. In particular, WO 2014/039637 states that “[W]while potentially lessening side effects and thereby enabling the use of higher and thus more effective doses of the AChEI, merely employing the concomitant use of antiemetics, such as domperidone and others, or of anticholinergics such as propantheline, oxybutynin, tolterodine and others, falls short of achieving the utmost therapeutic advantages of AChEIs in the treatment Alzheimer type dementias”.
However, U.S. Pat. No. 8,404,701 and, especially, WO 2014/039637, specifically exclude anticholinergic agents which are selective and/or non-peripheral because selective agents are not able to counteract the whole spectrum of the AChEIs' adverse effect and, worse, the non-peripheral anticholinergics, such as oxybutynin, are able to dangerously counteract the beneficial central action of said AChEIs.
Other literature discloses pharmaceutical compositions and Transdermal Therapeutic Systems (TTS) delivering oxybutynin through the human skin.
For example, U.S. Pat. Nos. 5,441,740 and 5,500,222, the disclosures of which are herein incorporated by reference in their entirety, disclose a patch for the transdermal administration of oxybutynin base using a monoglyceride or a mixture of monoglycerides of fatty acids as skin permeation-enhancer.
U.S. Pat. Nos. 5,686,097; 5,747,065; 5,750,137 and 5,900,250, the disclosures of which are herein incorporated by reference in their entirety, disclose a patch for the transdermal administration of oxybutynin base using a monoglyceride or a mixture of monoglycerides plus a lactate ester as skin permeation-enhancer.
A similar patch, adding a non-rate controlling tie layer on the skin-proximal surface of the reservoir, not affecting the drug release, is described in U.S. Pat. Nos. 5,614,211 and 5,635,203, the disclosures of which are herein incorporated by reference in their entirety.
U.S. Pat. Nos. 5,212,199, 5,227,169, 5,601,839 and 5,834,010, the disclosures of which are herein incorporated by reference in their entirety, disclose a patch for transdermal administration of basic drugs using triacetin as permeation enhancer.
U.S. Pat. No. 6,555,129, the disclosure of which is herein incorporated by reference in its entirety, discloses a TTS substantially consisting of an oxybutynin-containing matrix mass in the form of a layer which is self-adhesive, and in which the matrix mass consists of ammonium-group-containing (meth)acrylate copolymers, at least one citric acid triester and 5-25% by weight of oxybutynin.
U.S. Pat. No. 6,562,368, the disclosure of which is herein incorporated by reference in its entirety, discloses a method for transdermally administering oxybutynin using a composition in form of a patch, a cream, a gel, a lotion or a paste comprising oxybutynin and a hydroxide-releasing agent substantially consisting of inorganic hydroxides, inorganic oxides, metal salts of weak acids, and mixtures thereof.
U.S. Pat. Nos. 6,743,441; 7,081,249; 7,081,250; 7,081,251; 7,081,252 and 7,087,241, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal patch delivering a composition comprising oxybutynin to a subject to provide a plasma area under the curve ratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1, optionally in the presence of a permeation enhancer.
U.S. Pat. Nos. 7,029,694; 7,179,483; 8,241,662 and US 2009/0018190, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal gel formulation comprising oxybutynin providing a plasma area under the curve ratio of oxybutynin to an oxybutynin metabolite of from about 0.5:1 to about 5:1, optional in the presence of a permeation enhancer.
US 2004/0219194, the disclosure of which is herein incorporated by reference in its entirety, discloses a transdermal therapeutic system containing oxybutynin, triacetin and Aloe vera extract as permeation enhancer.
US 2004/0057985, the disclosure of which is herein incorporated by reference in its entirety, discloses transdermal therapeutic systems (TTS) for the administration of oxybutynin with which therapeutically active absorption rates can be achieved without the necessity of adding permeation-enhancing substances. These TTS comprise a substantially water vapor-impermeable backing layer, at least one pressure-sensitive adhesive matrix layer attached thereto, and a detachable protective film, said matrix layer comprising an inner phase containing the active substance oxybutynin, and an outer, pressure sensitive adhesive phase based on hydrocarbon polymers or/and silicone polymers.
US 2005/0064037, the disclosure of which is herein incorporated by reference in its entirety, discloses an oxybutynin gel formulation topical gel formulation comprising oxybutynin chloride salt, a short chain alcohol, a gelling agent substantially consisting of high-molecular-weight, cross-linked polymer of acrylic acid or cross-linked copolymer of acrylic acid and C10-30 alkyl acrylate, and optionally a permeation enhancer substantially consisting of propylene glycol, propylene glycol laurate, isopropyl myristate, and methyl lactate.
WO 2005/039531, US2007/022379, US 2010/0216880, US 2014/0037713 and U.S. Pat. No. 8,652,491, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal or transmucosal pharmaceutical formulation, that can be utilized for topical or transdermal application, such that solutions, creams, lotions, sprays, ointment, gels, aerosols and patch devices, for the delivery of one or more active agents, including anticholinergics, in particular oxybutynin. Said formulation includes oxybutynin in a solvent system comprising a diethylene glycol monoalkyl ether and a glycol in specific ratios, alcohol and water. In particular, according to U.S. Pat. No. 8,652,491 a possible secondary active agent, in addition to the anti-cholinergic agent such as oxybutynin, may be an antiperspirant, a tranquilizer or another agent capable of ameliorating hyperhidrosis. In addition, according to WO 2005/039531 the active agent may also be selected from an anti-Alzheimer's drug, in particular galantamine, rivastigmine, donepezil, tacrine, or memantine, without giving any indication of the doses to be used.
WO 2005/107812, U.S. Pat. No. 7,425,340 and US 2008/0260842, the disclosures of which are herein incorporated by reference in their entirety, disclose formulations containing an anticholinergic agent, in particular oxybutynin, in admixture with urea, urea congeners or urea-containing compounds as permeation enhancers.
WO 01/07018 and U.S. Pat. No. 8,420,117, the disclosures of which are herein incorporated by reference in their entirety, disclose a matrix patch formulation containing no water for external use, comprising, as essential components oxybutynin hydrochloride, citric acid and sodium acetate.
WO2013/061969 and US 2014/0271796, the disclosures of which are herein incorporated by reference in their entirety, disclose a transdermal absorption preparation comprising at least one drug selected from oxybutynin and pharmaceutically acceptable salts thereof; and a sterol such as cholesterol, cholesterol derivatives and cholesterol analogs.
U.S. Pat. No. 8,802,134, the disclosure of which is herein incorporated by reference in its entirety, discloses a method for producing a patch wherein oxybutynin is incorporated in an adhesive agent layer composition comprises the acrylic-based polymer as the adhesive base agent, and the acrylic-based polymer is a copolymer of polymethyl methacrylate with a polyacrylate.
U.S. Pat. No. 8,877,235, the disclosure of which is herein incorporated by reference in its entirety, discloses a patch consisting of a support layer and of an adhesive agent layer arranged on the at least one surface of the support layer, the adhesive agent layer comprising oxybutynin hydrochloride in a supersaturated concentration in a dissolved form. Said layer also comprises acrylic-based polymers and rubber-based polymers, as adhesive base agents, and liquid paraffin, a sterol, an organic acid, and a tackifier.
The disclosures of the aforementioned documents are incorporated herein by reference in their entirety.
Oxybutynin is a well-known non-selective anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and urge incontinence and all the above references emphasize this use. However, as set forth above, oxybutynin is not “peripheral” as per the definition given above because it is able to cross the blood brain barrier (“BBB”) to a non-negligible extent (Rebecca J McCrery and Rodney A Appell, Ther Clin Risk Manag. March 2006; 2/1: 19-24).
Oxybutynin is commercially presented in a patch releasing 3.9 mg/day oxybutynin (OXYTROL®). This patch provides significant improvements in all the measured parameters with less systemic adverse effects, as summarized by J. Jayarajan and S. B. Radomski in a review presented on 4 Dec. 2013: “Pharmacotherapy of overactive bladder in adults: a review of efficacy, tolerability, and quality of life” (J. Jayarajan et al., Research and Reports in Urology 2014:6), the disclosure of which is herein incorporated by reference in its entirety. However, oxybutynin is deemed to cross the BBB owing to its high lipophilicity, neutrality, and small molecular size (C. A. Donnellan et al. BMJ 1997; 315:1363-4; R. Scheife and M. Takeda, Clin Ther. 2005; 27:144-53), the disclosure of which is herein incorporated by reference in its entirety.
Oxybutynin is also commercially presented (GELNIQUE®) in a TTS consisting of a hydroalcoholic gel containing 100 mg oxybutynin chloride per gram of gel and available in a 1 gram (1.14 ml) unit dose. This TTS is deemed to have a pharmacokinetic profile similar to that of the patch delivery system, while producing lower N-desetyloxybutynin metabolite plasma concentrations (Vincent R Lucente et al.; Open Access Journal of Urology 2011/3, 35-42). Another commercial TTS system presents oxybutynin in a hydroalcoholic gel containing 30 mg oxybutynin base per gram of gel and is available (ANTUROL®) in a 0.92 gram (1 mL) unit dose that contains 28 mg oxybutynin per gram of gel. Also Anturol® demonstrated plasma levels of oxybutynin comparable to the efficacious plasma levels observed for oral and patch therapies with lower N-desethyloxybutynin plasma levels (Anturol® Gel Summary by Antares Pharma).
Oxybutynin is a very good tool for administering anticholinergic therapy but, even when given by transdermal route, it is deemed to induce adverse effects in the CNS, as per the warning that is present in the OXYTROL® label, and as reported in the literature. Indeed the current FDA product label for transdermal oxybutynin (Oxytrol®) states that nervous system side effects of Oxytrol® may include: Very common (10% or more): Dizziness, somnolence; Common (1% to 10%): Headache, mental/mood changes (such as confusion), insomnia, nervousness, convulsions, dysgeusia; and frequency not reported: paralysis, coma, CNS excitation. It further lists Central Nervous System Effects under Warnings and Precautions: “Products containing oxybutynin are associated with anticholinergic central nervous system (CNS) effects. A variety of CNS anticholinergic effects have been reported, including headache, dizziness, and somnolence. Patients should be monitored for signs of anticholinergic CNS effects, particularly after beginning treatment.” In addition, the label states that overdosage with oxybutynin has been associated with anticholinergic effects including CNS excitation and that CNS symptoms of overdose may include: memory loss, confusion, convulsions, dizziness, and drowsiness (severe). This possibility becomes a-priori, a material risk if it is intended to be used for the treatment of Alzheimer type dementia in combination with a CRA such as xanomeline, due to the competitive action of the two drugs inside the CNS.
U.S. Pat. No. 5,980,933, the disclosure of which is herein incorporated by reference in its entirety, discloses a transdermal xanomeline patch formulation comprising an effective amount of xanomeline, from 0.1 to 10 parts by weight azone, from 30 to 69.8 parts ethanol, 29 to 50 parts by weight water, from 0 to 30 parts by weight propylene glycol, and 1 to 5 parts by weight Klucel HF, also with about 70 to 99.8% acrylate adhesive. The literature only specifies that such a patch should have less adverse effects compared with the oral forms.
US 2011/0020423 discloses the combination of one or more muscarinic “Activators” (e.g., agonist, partial agonist, co-agonist, physiological agonist, potentiator, stimulator, allosteric potentiator, positive allosteric modulator or allosteric agonist) and one or more muscarinic “Inhibitors” (e.g., antagonist, partial antagonist, competitive antagonist, non-competitive antagonist, uncompetitive antagonist, silent antagonist, inverse agonist, reversible antagonist, physiological antagonist, irreversible antagonist, inhibitor, reversible inhibitor, irreversible inhibitor, negative allosteric modulator, or allosteric antagonist).
U.S. Pat. No. 8,853,219 discloses muscarinic agonists, which are useful for stimulating muscarinic receptors and treating cognitive disorders, said agonists including oxadiazole and oxathiazole derivatives, in particular 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine, also known as MCD-386, which is described in the literature for example in U.S. Pat. No. 5,403,845 to Dunbar, et al., 3-Methyl-5-(piperidin-3-yl)-1,2,4-oxadiazole), as a racemic mixture and as the single stereoisomers. This document also discloses combination compositions and co-administration comprising muscarinic agonists and antagonists, said muscarinic agonists including the substituted oxadiazoles and thiadiazoles disclosed therein and said muscarinic antagonists including atropine sulfate, N-methylatropine nitrate, flavoxate hydrochloride, N-methylscopolamine hydrochloride (methscopolamine), oxybutinin chloride, glycopyrrolate bromide, darifenacin hydrobromide, solifenacin succinate, propantheline bromide, trospium chloride, tolterodine tartrate, fesoterodine fumarate, methantheline bromide and combinations thereof. In terms of co-administration of a muscarinic-antimuscarinic combination, this document intends separate administration of agonist and antagonist, e.g., in separate dosage forms such as separate pills, separate injectable solutions or separate iontophoretic patches. According to this document, pharmacological tests made with a combination of representative oxadiazole muscarinic agonists with muscarinic antagonists showed that darifenacin and oxybutinin, both tertiary amines, are less effective than the other muscarinic antagonists by both oral and iontophoretic patch administration. In addition, this document observes that these drugs are known to penetrate the blood-brain barrier and may therefore inhibit the therapeutic effects of the agonist in the brain. Thus, this document, does not make any distinction among the peripheral/non-peripheral and selective/non-selective antimuscarinic agents.
In summary notwithstanding great scientific effort, the problem of the safe treatment of hypocholinergic disorders of the nervous system such as Parkinson's dementia, Lewy body diseases, Down Syndrome, and chronic neuropathic pain remains unsolved.